1. Field of the Invention
Apart from in pure research work, chemically synthesised oligonucleotides are being used increasingly in the industrial development of new biotechnological processes. The use of such nucleic acid fragments in the isolation, alteration (mutation) and total synthesis of genes, which carry the information for interesting proteins, or of DNA regions, which are responsible for regulating the expression of these proteins, opens up new possibilities for the microbiological production of such proteins.
2. Brief Description of the Prior Art
In the present context, oligonucleotides should be understood as being oligoribonucleotides and also oligodeoxyribonucleotides. The chemical synthesis of oligonucleotides is carried out in steps by linking suitably protected units or blocks which may comprise one or more nucleotides. Various methods of synthesis, which differ from one another in the chemistry of linking the 3'-5'-phosphodiester bond, belong to the prior art. Examples are:
(A) PA0 (B) PA0 (C)
phosphate diester method; cf. Nucleic Acids Research 10 (1982) 6553 to 6570, page 6553, line 10, PA1 phosphate triester method; cf. locus citatus, pages 6561 to 6562, PA1 phosphite triester method; cf. locus citatus, page 6563 PA1 linking of 5'-phosphates to 3'-hydroxyl groups; or PA1 linking of 3'-phosphates to 5'-hydroxyl groups; cf. locus citatus, page 6561 PA1 use of mononucleotides as blocks; PA1 use of dinucleotides as blocks; or PA1 use of blocks that comprise from more than two nucleotides up to oligonucleotides.
Rapid syntheses are carried out according to the Merrifield principle on a solid phase, the growing chains of the oligomer generally being bonded chemically, by their ends that are not being lengthened, to a solid phase in the form of a macroscopically solid support material. The chain-lengthening reactions or linking reactions are then carried out at the surface of the support material, the reaction product remaining bonded to the support and reaction excesses and reactants being removed by washing.
Hitherto, a large number of support materials have been used for such syntheses, it being necessary for the support material and the method of synthesis to be matched to one another; cf. locus citatus and literature indicated therein. The person skilled in the art is familiar with this matching procedure. Common to all of the support materials employed hitherto is that they are used in the form of granulates. For example, oligonucleotides have hitherto been synthesised individually on a small quantity of granulate. If n oligonucleotides having a chain length of m nucleotide units are to be manufactured according to this prior art, then n.times.m synthesis steps are necessary.